Genetic Variant GALNT3:p.Leu624Val (chr2-165748813-G-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_004482.4(GALNT3):c.1870C>G(p.Leu624Val) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,459,584 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L624F) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

GALNT3
NM_004482.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.62

Publications

0 publications found

Variant links:

Genes affected

GALNT3 (HGNC:4125): (polypeptide N-acetylgalactosaminyltransferase 3) This gene encodes UDP-GalNAc transferase 3, a member of the GalNAc-transferases family. This family transfers an N-acetyl galactosamine to the hydroxyl group of a serine or threonine residue in the first step of O-linked oligosaccharide biosynthesis. Individual GalNAc-transferases have distinct activities and initiation of O-glycosylation is regulated by a repertoire of GalNAc-transferases. The protein encoded by this gene is highly homologous to other family members, however the enzymes have different substrate specificities. [provided by RefSeq, Jul 2008]

GALNT3 Gene-Disease associations (from GenCC):

tumoral calcinosis, hyperphosphatemic, familial, 1
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae)
tumoral calcinosis, hyperphosphatemic, familial, 1
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, PanelApp Australia

GALNT3 links:

ENSG00000307262 (HGNC:):

ENSG00000307262 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.20779285).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GALNT3	NM_004482.4 link	c.1870C>G	p.Leu624Val	missense_variant	Exon 11 of 11	ENST00000392701.8	NP_004473.2	Q14435-1
GALNT3	XM_005246449.2 link	c.1870C>G	p.Leu624Val	missense_variant	Exon 11 of 11		XP_005246506.1	Q14435-1
GALNT3	XM_011510929.2 link	c.1870C>G	p.Leu624Val	missense_variant	Exon 11 of 11		XP_011509231.1	Q14435-1
GALNT3	XM_017003770.2 link	c.1870C>G	p.Leu624Val	missense_variant	Exon 11 of 11		XP_016859259.1	Q14435-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
GALNT3	ENST00000392701.8 link	c.1870C>G	p.Leu624Val	missense_variant	Exon 11 of 11	1	NM_004482.4	ENSP00000376465.3	Q14435-1
GALNT3	ENST00000409882.5 link	c.1084C>G	p.Leu362Val	missense_variant	Exon 8 of 8	1		ENSP00000386955.1	E7EUL0
GALNT3	ENST00000715282.1 link	c.1870C>G	p.Leu624Val	missense_variant	Exon 11 of 11			ENSP00000520447.1
ENSG00000307262	ENST00000824811.1 link	n.131-984G>C		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1459584

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726142

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33402

American (AMR)

AF:

0.00

AC:

AN:

44510

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26068

East Asian (EAS)

AF:

0.00

AC:

AN:

39616

South Asian (SAS)

AF:

0.00

AC:

AN:

86164

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53222

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5696

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1110612

Other (OTH)

AF:

0.00

AC:

AN:

60294

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.087

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.54

CADD

Benign

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.036

T;.

Eigen

Benign

-0.33

Eigen_PC

Benign

-0.10

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.84

T;T

M_CAP

Benign

0.0064

MetaRNN

Benign

0.21

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.28

N;.

PhyloP100

3.6

PrimateAI

Benign

0.41

PROVEAN

Benign

-0.060

N;N

REVEL

Benign

0.030

Sift

Benign

0.45

T;T

Sift4G

Benign

0.49

T;T

Polyphen

0.0010

B;.

Vest4

0.10

MutPred

0.27

Loss of ubiquitination at K626 (P = 0.1355);.;

MVP

0.35

MPC

0.096

ClinPred

0.41

GERP RS

3.8

Varity_R

0.10

gMVP

0.47

Mutation Taster

=93/7

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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2-165748813-G-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over